Our overall goal is to reduce the morbidity and mortality caused by ovarian cancer by developing a routine blood screen for earlier detection of incipient ovarian cancer when current therapies are most effective. The research described in this application is responsive to recommendations in the NCI report "New Directions in Ovarian Cancer." In the context of this proposal, ovarian cancer refers to tumors derived from the surface epithelium, so-called 'surface epithelial-stromal' in the World Health Organization's classification. Ovarian cancer is the most lethal of all gynecologic malignancies because most women present with disseminated disease that is rarely cured by current therapies. Conversely, primary tumor confined to the ovary (stage I) is treated quite successfully. Therefore early detection of ovarian cancer is critical. Unfortunately the diagnosis of early stage ovarian cancer is complicated by inaccessibility of the ovaries to direct examination, a lack of symptoms and absence of a sufficiently sensitive and specific screening test. The molecular changes associated with carcinogenesis induce aberrant gene expression and/or generate mutated gene products that are potentially antigenic. We have demonstrated that ovarian cancer patients generate autologous antibodies against such tumor antigens, and exploited these antibodies for expression cloning of tumor antigens. This technique, termed SEREX, is powerful because it identifies two types of potential biomarker; the SEREX antigen itself and the autologous antibody response specific for the SEREX antigen. Autologous antibodies to tumor antigens may be detectable in peripheral blood samples of patients with early stage ovarian cancer, and therefore represent promising biomarkers. We hypothesize that detection of autologous serum antibody reactive with appropriate SEREX antigens identifies patients with pre -cancerous or cancerous lesions. Therefore, Specific Aim 1 is to detect autologous serum antibodies against SEREX antigens of epithelial ovarian cancer by enzyme-linked immunosorbant assay (ELISA) and, in a case/control study, to evaluate their predictive value for detecting ovarian cancer. The predictive value of each marker will be compared to that of CA125, the only currently approved biomarker for ovarian cancer. Serum biomarker assays with promising specificity and sensitivity for stage I ovarian cancer will be developed for rapid clinical application.